Post

Response by the Author re: Kritzer et al. 2009

Joshua A Kritzer, PhD, NRSA Postdoctoral Fellow, Whitehead Institute for Biomedical Research
PARK1/4 (SNCA/Alpha-Synuclein), Therapeutic Development
Response to PD Guide:
Targeting Alpha-Synuclein
View all 4 responses to this PD Guide
Directly responding to:
Commentary on Kritzer et al. 2009
Targeting Alpha-Synuclein
Benjamin Wolozin, BU
13 Jul 2009 04:15 PM EST
In the current edition of Nature Chemical Biology, Dr. Lindquist's team reports a novel approach to identifying chemical inhibitors of protein toxicity.  This study has broad general relevance, ... 
Responses: 1

I appreciate Dr. Wolozin's enthusiasm for this technology -- we, too, hope that it will find great use both for diseases of poorly understood etiology such as PD as well as for other drug discovery and chemical biology applications.  I would like to clear up two points within Dr. Wolozin's response:

1.  A control cyclic peptide used the His-Pro-Gly motif to facilitate detection of the cyclic peptide in yeast lysates, but the cyclic peptides that are active in alpha-synuclein toxicity models do not have this motif.  We agree that the inability to confirm the relevant targets is frustrating, and one of the ways we are currently trying to streamline target ID using cyclic peptides is by adding this motif both to libraries and to selected hits to use as a pull-down handle.

2.  We did not reveal the identities of the targets we did pull down because we were not convinced, based on subsequent genetic modulation of those targets, that they were the relevant targets that mediate the action of cyclic peptides that reduce alpha-synuclein toxicity.  As noted in the paper, we are performing second-generation selections to generate more potent cyclic peptide constructs, as well as performing hypothesis-based testing of suspected modes of action to try to uncover how these cyclic peptides rescue alpha-synuclein toxicity (apparently without rescuing the trafficking defects!).  Stay tuned indeed -- we hope you will!

Dr. Wolozin is spot-on regarding the future directions of this technology.  The selection method can indeed be applied to a great many targets suspected in mechanisms of disease.  While it is currently possible to translate peptide ligands to more drug-like molecules, it requires a large traditional medicinal chemistry effort and a lot of trial-and-error.  Thus, it will also be a very active area of research in coming years to develop more general methods for modifying cyclic peptides to allow exogenous application of the peptides and to allow more rapid development of cyclic peptides as therapeutics.

 

 

 

 

 

Reference: 
Kritzer JA, Hamamichi S, McCaffery MJ, Santagata S, Naumann TA, Caldwell KA, et al. Rapid selection of cyclic peptides that reduce alpha-synuclein toxicity in yeast and animal models. Nat Chem Biol. 2009;5(9):655-63.
Reply